DNA Cleavage and Detection of DNA Radicals Formed from Hydralazine and Copper (II) by ESR and Immuno-Spin Trapping

Sinha, Birandra K.; Leinisch, Fabian; Bhattacharjee, Suchandra; Mason, Ronald P.

doi:10.1021/tx500011m

Cited by 17 publications

(14 citation statements)

References 58 publications

(138 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After introducing Cu(OTf) 2 into the reaction system (Notably, other metal salts were also tested, see Figs S1 and S2 in supplementary information for details), the desired nitrogen-centered radical was successfully detected ( Fig. 5B ) 52 53 , where the g factor was 2.0059. The above results might demonstrate the existence of nitrogen-centered radical and stabilization effect of Cu(OTf) 2 to nitrogen-centered radical.…”

Section: Resultsmentioning

confidence: 99%

Tuning the Reactivity of Radical through a Triplet Diradical Cu(II) Intermediate in Radical Oxidative Cross-Coupling

Zhou

Zhu

et al. 2015

Sci Rep

View full text Add to dashboard Cite

Highly selective radical/radical cross-coupling is paid more attention in bond formations. However, due to their intrinsic active properties, radical species are apt to achieve homo-coupling instead of cross-coupling, which makes the selective cross-coupling as a great challenge and almost untouched. Herein a notable strategy to accomplish direct radical/radical oxidative cross-coupling has been demonstrated, that is metal tuning a transient radical to a persistent radical intermediate followed by coupling with another transient radical. Here, a transient nitrogen-centered radical is tuned to a persistent radical complex by copper catalyst, followed by coupling with a transient allylic carbon-centered radical. Firstly, nitrogen-centered radical generated from N-methoxybenzamide stabilized by copper catalyst was successfully observed by EPR. Then DFT calculations revealed that a triplet diradical Cu(II) complex formed from the chelation N-methoxybenzamide nitrogen-centered radical to Cu(II) is a persistent radical species. Moreover, conceivable nitrogen-centered radical Cu(II) complex was observed by high-resolution electrospray ionization mass spectrometry (ESI-MS). Ultimately, various allylic amides derivatives were obtained in good yields by adopting this strategy, which might inspire a novel and promising landscape in radical chemistry.

show abstract

Section: Resultsmentioning

confidence: 99%

Tuning the Reactivity of Radical through a Triplet Diradical Cu(II) Intermediate in Radical Oxidative Cross-Coupling

Zhou

Zhu

et al. 2015

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Interestingly, previous studies have shown that hydralazine exposure induced both DNA cleavage and damage [24, 25]. The lack of efficient DNA repair is often an advantage for cancer therapy (especially radio- and chemotherapy), based on the concept of synthetic lethality, which states that cancer cells are more proliferative and thus more susceptible to induced DNA damage than normal cells.…”

Section: Discussionmentioning

confidence: 99%

Anti-neoplastic properties of hydralazine in prostate cancer

et al. 2014

View full text Add to dashboard Cite

Prostate cancer (PCa) is a major cause of cancer-related morbidity and mortality worldwide. Although early disease is often efficiently managed therapeutically, available options for advanced disease are mostly ineffective. Aberrant DNA methylation associated with gene-silencing of cancer-related genes is a common feature of PCa. Therefore, DNA methylation inhibitors might constitute an attractive alternative therapy. Herein, we evaluated the anti-cancer properties of hydralazine, a non-nucleoside DNA methyltransferases (DNMT) inhibitor, in PCa cell lines. In vitro assays showed that hydralazine exposure led to a significant dose and time dependent growth inhibition, increased apoptotic rate and decreased invasiveness. Furthermore, it also induced cell cycle arrest and DNA damage. These phenotypic effects were particularly prominent in DU145 cells. Following hydralazine exposure, decreased levels of DNMT1, DNMT3a and DNMT3b mRNA and DNMT1 protein were depicted. Moreover, a significant decrease in GSTP1, BCL2 and CCND2 promoter methylation levels, with concomitant transcript re-expression, was also observed. Interestingly, hydralazine restored androgen receptor expression, with upregulation of its target p21 in DU145 cell line. Protein array analysis suggested that blockage of EGF receptor signaling pathway is likely to be the main mechanism of hydralazine action in DU145 cells. Our data demonstrate that hydralazine attenuated the malignant phenotype of PCa cells, and might constitute a useful therapeutic tool.

show abstract

“…4a ) was a triplet-of-sextets (blue line in Fig. 4b ) with HFCs of a N = 13.58 G, a H = 16.64 G, a γ−N = 2.50 G; this signal was assigned to a DMPO-trapped N-centered radical adduct (DMPO-N·) 31 32 . The small γ-N hyperfine coupling constant clearly indicated the existence of the Co-diazo radical.…”

Section: Resultsmentioning

confidence: 99%

Metal-Diazo Radicals of α-Carbonyl Diazomethanes

Xiao

Liu

2016

Sci Rep

View full text Add to dashboard Cite

Metal-diazo radicals of α-carbonyl diazomethanes are new members of the radical family and are precursors to metal-carbene radicals. Herein, using electron paramagnetic resonance spectroscopy with spin-trapping, we detect diazo radicals of α-carbonyl diazomethanes, induced by [Rh Radicals are highly reactive intermediates, long sought because of their importance in understanding reaction mechanisms and finding new reactions 1 . However, their extremely short lifetimes make their direct detection difficult and impede the development of radical chemistry. Carbenes, from nitrogen-releasing diazo compounds 2 , are the versatile active species in a broad range of reactions, including C-H functionalization 3,4 , carbon-carbon bond formation 5,6 , cyclopropanation 7,8 and polycarbene construction 9-11 . Usually, these reactions are carried out with metal catalysts, and the intermediates, generally considered to be metal-carbenes, have attracted much attention over the past decade [12][13][14][15][16] . Recent studies have shown that some metal-carbenes within paramagnetic metal catalysts (such as Co II , Rh II , and Ir II ) are carbon-centered metal-carbene radicals, not closed-shell metal-carbenes [17][18][19] . As such, their metal-diazo-adduct precursors are reasonably postulated to also possess radical character.Because of the vigorous N 2 evolution and high efficiencies of these reactions, few studies have reported such radicals [20][21][22][23] . The EPR signals of some diazo radical cations of diphenyldiazomethanes and their derivatives have been recorded after electrochemical oxidation or irradiation in Freon matrices [24][25][26] . In frozen toluene at 40 K, a carbon-centered Co-carbene radical was detected by EPR spectroscopy, along with several other paramagnetic cobalt species 17 , which complicated the spectral analysis. Diazo radicals may coexist with carbene radicals within reaction systems, and distinguishing them from one another is likewise difficult. Thus, the detection of metal-diazo radicals and their transformations into metal-carbene radicals remain unsolved challenges in diazo chemistry.To overcome these challenges, we employed room-temperature electron paramagnetic resonance (RT-EPR) spectroscopy with a spin-trapping technique 27 , which offers a convenient and powerful way to identify both diazo radicals and carbene radicals and to simultaneously investigate their behaviors. Because of the persistent radical effects of the redox-active metal and nitroxide 1 , the transient radical intermediates can be either directly detected by EPR or captured by radical traps (Fig. 1). In this paper, we report that the use of [RhCl(cod)] 2 (cod = 1,5-cyclooctadiene) allowed the RT-EPR detection of a rather stable dinitrogen radical of α -carbonyl diazomethane as a unique quintet signal. Density function theory (DFT) calculations support the EPR analyses, assigning a significant amount of spin density (97.2%) to the diazo moiety. To our knowledge, this work represents the first unequivocal spectroscopic confi...

show abstract

DNA Cleavage and Detection of DNA Radicals Formed from Hydralazine and Copper (II) by ESR and Immuno-Spin Trapping

Cited by 17 publications

References 58 publications

Tuning the Reactivity of Radical through a Triplet Diradical Cu(II) Intermediate in Radical Oxidative Cross-Coupling

Tuning the Reactivity of Radical through a Triplet Diradical Cu(II) Intermediate in Radical Oxidative Cross-Coupling

Anti-neoplastic properties of hydralazine in prostate cancer

Metal-Diazo Radicals of α-Carbonyl Diazomethanes

Contact Info

Product

Resources

About